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Abstract
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis. Although AMPK has been studied extensively in cellular processes, understanding of its substrates and downstream functional network, and their contributions to cell fate and disease development, remains incomplete. To elucidate the AMPK-dependent signaling pathways, we performed global quantitative phosphoproteomic analysis using wild-type and AMPKα1/α2-double knockout cells and discovered 160 AMPK-dependent phosphorylation sites. Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion.
Highlights
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis
To determine whether Armadillo repeatcontaining protein 10 (ARMC10) is involved in these mitochondrial transitions, we examined microtubule-associated protein 1 light chain 3 (LC3) staining as a marker of autophagy
We found that ARMC10 can interact with two mitochondrial fission proteins, mitochondrial fission factor (MFF) and FIS1, that are important in mediating Drp[1] recruitment during mitochondrial fission[41], but no obvious binding was noted between ARMC10 and the two mitochondrial fusion proteins MFN1 and OPA1 (Fig. 6b)
Summary
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a kinase complex that acts as a central regulator of cellular energy homeostasis in eukaryotes. When the ratios of AMP:ATP and ADP:ATP increase, AMPK is activated and controls the activities of enzymes in a variety of pathways to ensure energy homeostasis. AMPK phosphorylates 3-hydroxy-3-methyl-glutaryl–coenzyme A reductase and glycerol-3-phosphate acyltransferase to block the synthesis of sterols and triglycerides, respectively[2] These regulatory actions by AMPK ensure increased cellular ATP supplies and decreased ATP consumption. James and colleagues reported on their global phosphoproteomic analysis of acute exercise signaling in human skeletal muscle and performed additional targeted
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